Hungry for your alanine: when liver depends on muscle proteolysis
Theresia Sarabhai, Michael Roden
Theresia Sarabhai, Michael Roden
Published September 23, 2019
Citation Information: J Clin Invest. 2019;129(11):4563-4566. https://doi.org/10.1172/JCI131931.
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Commentary

Hungry for your alanine: when liver depends on muscle proteolysis

Abstract

Fasting requires complex endocrine and metabolic interorgan crosstalk, which involves shifting from glucose to fatty acid oxidation, derived from adipose tissue lipolysis, in order to preserve glucose for the brain. The glucose-alanine (Cahill) cycle is critical for regenerating glucose. In this issue of JCI, Petersen et al. report on their use of an innovative stable isotope tracer method to show that skeletal muscle–derived alanine becomes rate controlling for hepatic mitochondrial oxidation and, in turn, for glucose production during prolonged fasting. These results provide new insight into skeletal muscle–liver metabolic crosstalk during the fed-to-fasting transition in humans.

Authors

Theresia Sarabhai, Michael Roden

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Figure 1

Liver–skeletal muscle crosstalk fuels metabolism in starvation.

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Liver–skeletal muscle crosstalk fuels metabolism in starvation. The Cahi...
The Cahill cycle allows for recycling of hepatic glucose from skeletal muscle alanine via ALT and for detoxification of ammonium ions (NH4+) from proteolysis via the hepatic urea cycle. In 60-hour fasted humans, the nearly unchanged gluconeogenesis, as assessed from VPC, indicates that reduced hepatic glycogenolysis accounts for the decrease in VEGP. The decrease in VCS occurred in parallel to a rise in the β-hydroxy-butyrate/acetoacetate ratio (β-OHB/AcAc) suggesting that the redox potential regulates VCS. Of note, alanine infusion partially reversed these alterations under conditions of already stimulated hepatic mitochondrial oxidation resulting from substrate supply and endocrine stimulation. CI, citrate; FA-CoA, fatty acyl–coenzyme A; GH, growth hormone; α-KG, α-ketoglutarate; βOX, β-oxidation; OA, oxaloacetate; PEP, phosphoenolpyruvate; PEPCK, PEP carboxykinase; TAG, triglycerides; T3, triiodothyronine.